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Extrapulmonary Tuberculosis

Randall Reves, MD, Colorado University Denver, volunteer TB Clinician Denver Metro TB Control Program

Slides adapted from originals by Timothy H. Dellit, MD, Harborview Medical Center

No financial conflicts

US Reported TB Cases by Site1993-2006 (14 yrs)

Total US reported cases – 253,299 EPTB only – 47,293 (19%) Both EPTB & PTB – 14,910 (6%) Disseminated TB – 4,478 (2%)

PTB only – 186,540 (74%) Unknown - < 1%

Peto, et. al CID 2009;49:1350-7

Peto. CLIN INFECT DIS 49(9):1350-1357. 2009

Extrapulmonary TB, U.S. 1993-2006 (n=47,293, 19% of cases))

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Incidence of Pulmonary vs. Extrapulmonary TB

Clin Infect Dis 2009;49:1350-7

CDC Reported Tuberculosis in the United States 2014

Nationally: Pulmonary 69%, EXPTB 21%, Both 10%

Extrapulmonary TB and Vitamin D Deficiency?

Birmingham UK 1980-2009US CDC 1993-2008

Extrapulmonary disease associated with: Female gender Non-white ethnicity Foreign-born Vitamin D deficiency

Doubling serum 25(OH)D reduced risk (OR 0.55 CI 0.41 to 0.73)

Thorax 2015;70:1171-1180

Mycobacterium bovis: more likely extrapulm. but most still pulmonary

Clin Infect Dis 2008;47:168-175

• Part of MTB complex• 1-2% of human

tuberculosis in US due to M. bovis

• Unpasteurized dairy• Mono-resistance to PZA

Emerg Infect Dis 2015;21:435-443

62.5% pulm.

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Thoracentesis:• 1200 WBC 88% lymphs • Total protein 5.4• LDH 358

35 year old Vietnamese man in ED: 3 weeks of worsening non-productive cough, fever, night sweats, and right-sided chest pain.

40 y.o. homeless woman with TST conversion but no symptoms

April ‘09 April ‘09

40 y.o. homeless woman: pleural bx non-diagnostic, sputum sm (-)/cult +

April ‘09 July ‘09

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Diagnosis of Pleural TBDiagnostic Approach SensitivityPleural fluid culture 10-40%

Pleural biopsy culture 55-85%

Pleural biopsy histology 50-80%

Combined pleural biopsyculture and histology

80-95%

Other tests:• PCR

• Pleural fluid-Sensitivity 62%, specificity 98%-More sensitive in cases of culture-positive pleural fluid

• Pleural biopsy sensitivity 90%, specificity 100% • Adenosine deaminase (ADA)

• Sensitivity 92%, specificity 90% Respir Med 2008;102:744-54BMC Infect Dis 2004;4:6Chest 2003;124:2105-11

43 y o woman from Eritrea with 3 week h/onon-productive cough, fever, and night sweats

Now What?

AFB smear neg x 5 (3 sputum, 2 BAL)

Sputum PCR neg

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Miliary Tuberculosis Lymphohematogenous

dissemination Millet seeds in lungs*◦ Impaired diffusion

◦ Sputum smear positive in 1/3

High blood flow organs◦ Spleen, liver*, bone marrow*,

kidneys*, adrenals

Meningitis* in 10-30%

Increased TST anergy

*Potential positive specimens: sputum, BAL, urine, stool, CSF, tissue biopsies, rarely blood

Lancet Infect dis 2005;5:415-30

42 y.o. man with chronic renal failure

Chronic hemodialysis for polycystic disease

Hepatitis C due to IDU Hospitalized from prison for fever and

hemoptysis Left pleural effusion developed Fever persistent despite ceftriaxone &

azithro Worsening anemia, mild pancytopenia,

rising alkaline phosphatase

42 y.o. man with chronic renal failure

Sputum AFB smear & culture negative

PPD 8 mm Transudative pleural

fluid – not cultured for TB

Bone marrow biopsy neg for granuloma –no AFB culture done!

Discharged after response to levofloxacin

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42 y.o. man with CRF: clues for TB

Right apical scar Rising alk phos –?

granulomatous hepatitis

Liver biopsy recommended

43 y.o. with CRF: readmitted 2 wks later liver biopsy done transjugular: granulomas, AFB stain & culture-negative

43 y.o. man with CRF treated empirically for TB

Symptoms resolved Anemia improved Alkaline phos returned to normal All cultures remained negative Reported as a clinical case of TB

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47 yr old woman

Swollen cervical lymph node x 1 month

Denies other symptoms

Born in Vietnam and previously treated for TB 20 years ago

47 yr old female: sputum negative

Node biopsy is smear (+) and confirms INH resistant TB

HIV (-)

6 weeks into therapy, the inflammation is worse

47 yr old female: needle drainage

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Cervical Tuberculous Lymphadenopathy

Importance of epidemiology Often multiple-matted lymphnodes FNA sensitivity > 90% Medical therapy for 6 months Paradoxical reaction in 20%

Postgrad Med J 2001;77:185-7

Clin Infect Dis 2011;555-562

0

20

40

60

80

100

Sym

ptom

s %

CSF WBC 338 L60, protein 136, glucose 32

CSF HSV negative

CSF TB PCR negative

19 y o man from Guatamala with “fainting spell” 2 weeks PTA, then progressive frontal headaches with nausea and emesis.

PE: T 39.6, left VI nerve palsyMRI with leptomeningeal enhancement in left temporal lobe

CSF Characteristics

Characteristic CNS TB HSV-1 Enterovirus

No. Cases 20 39 44

CSF leukocytes per ml, median 201 47 85

CSF protein, mg/dl, median 174 71 60

CSF glucose, mg/dl, median 35 69 67

Emerg Infect Dis 2008;14:1473-5

California Encephalitis Project

• 20 CNS TB cases all culture positive• 4/17 (24%) CSF TB PCR positive

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75 y.o. Peruvian-born woman with erythema induratum for 6 years

May ‘09 Nov ‘09

75 y.o. woman: cultures negative, response to IRE for 2 mo., IR for 4

Nov ‘09

IGRAs and Extrapulmonary TB

Sensitivity Specificity

QFT-Ga 69% 82%

QFT-2Gb 86% 84%

TSTb 57% 49%

aDiagn Microbiol Infect Dis. 2009;63:182-7

bRespirology 2009;14:276-81

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Pulmonary Involvement in Extrapulmonary TB

• 72 patients with XPTB36 lymph nodes12 pleura6 CNS6 GI

• 57 had sputum collection

• Weight loss associated with positive sputum cxOR 4.3 (1.01-18.72)

Chest 2008;134:589-9449% had abnormal CXR

0%

5%

10%

15%

20%

25%

Xpert MTB/RIF for Extrapulmonary TB

Eur Respir J 2014;44:435-446Ann Intern Med 2015;162:JC11

Meta-analysis of 18 studies and 4461 samples

WHO 2013Xpert MTB/RIF should be used in preference to conventional microscopy and culture as the initial diagnostic test for CSF specimens from patients suspected of having TB meningitis (alternative for lymph nodes and other tissues)

19 y o man from Philipines presented with 8 weeks of HA and progressive LE weakness

CSFWBC 120, 90LProtein 1500Glucose 40

MRI with extensive basal leptomeningeal enhancement

Role of intrathecal therapy?Role of CSF drug levels?

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TB Drugs and CNS

INH & PZA - bactericidal and penetrate inflamed and uninflamed meninges

RIF, streptomycin & EMB - do not penetrate uninflamed meninges as well

Fluoroquinolones penetrate CSF

Is there a role for treatment intensification” Higher dose RIF, adding FLQ?

Continuing PZA and/or adding cycloserine or ethionamide throughout 9 months of therapy?

Intensified Initial Therapy in TB Meningitis: No Benefit

N Engl J Med 2016;374:124-134

Randomized, double-blind, placebo controlled study in Vietnam, n=817, 43% HIV+

Standard Therapy 3 monthsINHRifampin (10 mg /kg)PZAEthambutol

Followed by 7 months INH and rifampinAll received dexamethasone for 6-8 weeks

Mortality 28% in STD and IntensiveNote: INH-res.: 39% (16/41) vs 24% (11/45),

p=0.06

Intensified8 weeksRifampin 15 mg/kgLevo 20 mg/kg

CNS TB and Paradoxical Response Balance between host immunologic response and

direct effects of mycobacterial products◦ Neurological decline

◦ Increase in size, number, or appearance of tuberculomas

◦ Typically occur within 3 months of therapy

◦ In setting of tapering or discontinuing steroids

Does not represent failure of therapy◦ Do not need to change regimen

TB meningitis◦ May be associated with neutrophilic predominance

◦ More frequent development of tuberculomas

Clin Infect Dis 1994;19:1092-9Infection 2003;31:387-91

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33 y.o. man with LTBI & DM

TST 16 mm 7 yrs ago Developed diabetes mellitus Started on INH with 25 mg pyridoxine Had a seizure at home after 2 weeks PCP thought cause was hypoglycemia Repeat seizure 3 weeks later

33 y.o. with 2nd seizure

33 y.o. on INH with brain mass

Seizures controlled with phenytoin Tuberculoma removed at craniotomy AFB stains negative IRZE started post-op Are there drug interactions to consider?

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29 y o man from Somali presents with seizures, chronic back pain, and difficulty urinating

Pott’s Disease with Paravertebral Abscess

• Classically begins with anterior vertebral body and disk• Progressive collapse, anterior wedging, and gibbus formation• Posterior involvement of vertebral arch and spinous process

N Am J Med Sci 2013; 5: 404–411

Spinal Tuberculosis Accounts for 50% of skeletal tuberculosis◦ Hip 15%, knee 10%

Hematogenously spread◦ Batson’s plexus

Paucibacillary disease, slow growing◦ 12-18 months of therapy

Medical therapy alone curative > 90%◦ Surgery limited to neurologic compromise, spinal stability,

tissue diagnosis

◦ MRI may initially demonstrate increase in bony destruction and size of abscess despite clinical improvement

Clinical Orthopaedics and Related Research 2007;460:29-38Clinical Orthopaedics and Related Research 2002;398:11-19

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44 y o Vietnamese man with 6 month h/o pain and swelling of left medial thigh associated with fevers and night sweats

Also 2 month h/o fever, night sweats, 15 lb wt loss, and dry cough

27 y o man from Ethiopia with 2 day h/o severe abdominal pain, nausea and emesis

Could he have pulmonary involvement?

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Tuberculosis of Small Bowel Pathogenesis◦ Swallowing infected sputum◦ Ingestion of contaminated milk◦ Hematogenous spread◦ Direct extension

Ileocecal and jejuno-ileum most common sites Patterns◦ Ulceroconstrictive lesions, with perforation and fistulae in 5%◦ Obstruction in 20%◦ Right lower quadrant abdominal mass 25%◦ “Doughy abdomen” classic, but less common

Mimics◦ Periappendiceal abscess, Crohn’s disease, Yersinia, Amebiasis

Peritoneal Tuberculosis

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20

40

60

80

100Ascitic Fluid

Exudative • Lymphocytic pleocytosis• Protein > 2.5 – 3 g/dl• SAG < 1.1 g/dl

Diagnositics• AFB smear < 3%• AFB culture 20-83%• ADA 93-100%• Laparoscopy with biopsy 85-95%

Am J Gastroenterol 1993;88:989-99Colorectal Dis 2007;9:773-83

Sym

ptom

%

96 y.o. woman: nursing home pneumonia BAL culture: K.

pneumonia Living independently till

admission 3 mo. earlier for “failure to thrive” –pancreatic mass, no biopsy

Imipenem/cilastin + gentamicin

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96 y.o. woman: nursing home pneumonia

Improved over 1 wk Expired on 9th day BAL culture grew M.

tuberculosis, drug-susceptible

No known TB exposure

Visited twin sister in IL one month prior to health deterioration

96 y.o. woman: presumptive pancreatic TB

Complex mass/fluid extending into LUQ, ? infection

Mass contained calcifications, consistent with pancreatic TB

Assessment: death due to pancreatic TB with dissemination; probably infected in childhood

25 y o man from Mexico with 2 month history of fever, chills, night sweats, cough, and 30 lb wt lossAlso dysuria with 3+ WBC and RBC

Sputum 4+ AFB

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Urogenital Tuberculosis

May present with dysuria, hematuria, or flank pain Asymptomatic patients with classic sterile pyuria Men◦ Kidney, prostate, seminal vesicles, epididymis, testes◦ Oligospermia

Women◦ Endosalpinx with spread to peritoneum, endometrium, ovaries,

cervix, vagina◦ Pelvic pain, infertility, vaginal bleeding

Mycobacterial culture of early morning urine specimens

Am Fam Physician 2005;72:1761-8

Tuberculous Meningitis and Steroids

RR CI

Death 0.78 0.67-0.91

Stage 1 (mild) 0.52 0.30-0.89

Stage 2 (moderate) 0.73 0.56-0.97

Stage 3 (severe) 0.70 0.54-0.90

Death or disabling neurologic deficit 0.82 0.70-.0.97

Death stratified by HIV status 0.82 0.66-1.02

Cochrane Database Syst Rev. 2008 Jan 23;(1):CD002244

Seven Randomized Studies

Tuberculous Meningitis and Steroids

• 545 patients randomized to double-blind placebo controlled study of adjunctive dexamethasone with 5 year follow up (9.2% lost)• Two-year survival: 0.63 vs. 0.55 (p=0.07)• Five-year survival: 0.54 vs. 0.51 (p=0.51)

PLoS One 2011;6:e27821

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TB Pericarditis and Steroids:Changing recommendationsMulticenter randomized study comparing prednisolone vs. placebo in 1400 adults with TB pericarditis

NEJM 2014;371:1121-30

80 y.o. Cambodian-born woman in US 30 yrs4 months s/p 2nd CABG & Mitral Valve Repl.

High-pressure fluid collection in pacemaker pouch• Epicardial wires

removed• M.tb on culture

Presumed origin: pericardial TB

Kestler, Int J TubercLung Dis. 2009

Summary

Tuberculosis can occur anywhere within the body Diagnosis can be extremely challenging◦ Microbiology◦ Pathology

◦ Nucleic amplification

◦ TST vs. interferon-gamma release assays?

Evaluate for pulmonary disease Coordinated management with public health